madman
Super Moderator
Bipolar Androgen Therapy Followed by Androgen Receptor Inhibition as Sequential Therapy for Prostate Cancer (2023)
Samuel R. Denmeade*,Laura A. Sena, Hao Wang, Emmanuel S. Antonarakis, Mark C. Markowski
Abstract
Inhibition of androgen receptor (AR) signaling has been the mainstay of treatment of advanced prostate cancer (PCa) for the past 80 years. Combination and sequential AR-inhibiting therapies are highly effective palliative therapy, but they are not curative. All patients eventually develop resistance to primary castrating therapy [ie, castration-resistant PCa (CRPC)]. At this point, they are treated with subsequent lines of secondary AR inhibitory therapies. However, resistance to these agents also develops and patients progress to a state we have termed complete androgen inhibition-resistant PCa. This phase of the disease is associated with poor prognosis. At this point, treatment shifts to non-hormonal cytotoxic therapies (eg, chemotherapy and radiopharmaceuticals). However, the majority of PCas remain addicted to signaling through AR throughout the course of the disease. Resistant PCa cells adaptively upregulate AR activity, despite castration and AR inhibitors, via mechanisms such as AR overexpression, gene amplification, mutation, and expression of ligand-independent variants to permit sustained liganded and non-liganded AR signaling. Studies dating back nearly 30 years indicate that high expression of AR induced by prolonged castration becomes a vulnerability of CRPC cells in vitro and in mouse xenografts to supraphysiologic androgen (SPA), which induces cell death and growth arrest in this context. Based on these studies, we developed a counterintuitive treatment called bipolar androgen therapy (BAT) for patients with CRPC, in which SPA is administered intermittently to result in the cycling of serum testosterone from the polar extremes of supraphysiologic to near-castrate levels. This rapid cycling is intended to disrupt the adaptive AR regulation associated with chronic exposure to high or low levels of testosterone, while simultaneously targeting the spectrum of AR expression present in heterogeneous CRPC tumors. We have now tested BAT in >250 patients with CRPC. Here we present a review of these clinical studies, which have demonstrated collectively that BAT can be safely given to men with CRPC, improves the quality of life, and produces therapeutic responses in ~30% of patients. As expected, resistance to BAT is associated with adaptive downregulation of AR expression. Intriguingly, this downregulation is associated with the restoration of sensitivity to subsequent AR inhibitor therapies.
Introduction
The Current Treatment Paradigm
In 1941, Dr. Charles Huggins reported on the remarkable palliative benefit of surgical and medical castration in men with symptomatic, metastatic prostate cancer (PCa). Since that discovery, inhibition of androgen receptor (AR) function through androgen deprivation (ADT) and direct AR inhibition has remained the mainstay of treatment.1,2 The current treatment paradigm for metastatic PCa is to treat men with ADT in combination with AR signaling inhibitors (ARSI) or chemotherapy until disease progression. From the very outset of ADT use, it was recognized that all men eventually develop resistance to primary ADT, a disease stage known as castration-resistant PCa (CRPC). This resistance was presumed to be due to sustained AR signaling via non-prostate sources of androgens.2 Once the patient develops CRPC, additional AR inhibiting therapies are administered with decreasing effectiveness as more lines of therapy are given.3,4 In addition to therapeutic resistance, chronic exposure to ADT leads to excess morbidity and, in a subset of men, may lead to transdifferentiation to a more aggressive and lethal neuroendocrine phenotype.5
A number of ARSIs have been developed as first-line therapy in combination with or after ADT aimed at further blocking androgen signaling through AR.6 These include the CYP17 androgen-synthesis inhibitor abiraterone and antiandrogens enzalutamide, apalutamide, and darolutamide. Both abiraterone and enzalutamide received initial FDA approval based on modest survival benefit vs. placebo in men with mCRPC post-chemotherapy and subsequently in men treated pre-chemotherapy based on the results of the COU-AA-302 (abiraterone) and PREVAIL (enzalutamide) studies, Table 1. 7-10
The effectiveness of first-line combination androgen blockade was revisited with multiple trials such as LATITUDE (abiraterone), STAMPEDE (abiraterone), ARCHES (enzalutamide), and TITAN (apalutamide) each demonstrating a significant survival advantage for combination therapy compared to ADT alone in men with high risk and metastatic PCa.11-14 Recent results from the ARASENS trial also demonstrated a survival advantage for “triplet” therapy consisting of ADT + docetaxel + darolutamide vs. the “doublet” of ADT + docetaxel.15 While these trials have shown significant improvement in survival vs. the control arm, once patients develop radiographic progression, survival is relatively short with a median duration of survival in the range of 18-24 months.11,12
Additionally, emerging data documents a significant reduction in response rate and response duration with sequential use of abiraterone or enzalutamide as “second or third-line” ARSI therapy. Results from a series of small studies evaluating the use of enzalutamide after progression on abiraterone show a marked decrease in PSA PFS, time to progression, and objective response.16-19 Broadly, ~95% of patients respond to initial androgen ablative therapy, with ~65% response to first-line ARSI and ~25% response to second and further lines of ARSI therapy. Evaluation of patient biopsies and autopsy studies demonstrates that CPRC cells resistant to ARSI continue to engage in AR signaling and adapt to chronic exposure to low testosterone through a progressive, auto-regulatory increase in AR expression to sufficient levels to restore AR axis activity even in the absence of ligand.20-22 At each stage, resistance first manifests as a sustained rise in the androgen-responsive gene PSA, consistent with the reactivation of a functioning AR axis.
Rationale for Supraphysiologic Testosterone as Therapy for CRPC
A major factor driving resistance to ADT is the ability of PCa cells to adapt to chronic low androgen conditions by upregulating AR activity through overexpression, gene amplification, and expression of transcriptionally active AR variants that lack the ligand-binding domain, Fig. 1A, 1B. 23-27 Data from a variety of studies has demonstrated that AR expression persists even in men with CRPC who have died from PCa despite having received chronic ADT and multiple types of ARSI.20,25 Chen et al. demonstrated that PCa cell lines adapt to serial passage in castrated mice through an auto-regulatory increase in AR expression that is sufficient to induce resistance to both ADT and the anti-androgen bicalutamide.28 Isaacs et al. documented that AR levels increased 30-90 fold in CRPC cell lines and clinical samples compared to normal prostate cells.29 While this marked upregulation of AR can drive resistance to ADT, it also creates a therapeutic vulnerability to treatment with supraphysiologic androgen (SPA).28-30 SPA can lead to growth arrest or cell death in CRPC cell models. This paradoxical effect initially was extensively demonstrated by the work of Dr. Shutsung Liao, whose laboratory showed that PCA cells adapted to grow in low androgen conditions had high AR levels and were growth-inhibited by SPA in vivo.31 Over time, these xenografts became resistant to SPA through downregulation of the AR, making them once again sensitive to ADT.
Several complementary mechanisms for this paradoxical effect of SPA have been described. Isaacs et al. demonstrated that AR is a DNA licensing factor that plays a critical role in DNA replication and must be degraded as the cell goes through cycle.21,22,29 AR over-stabilization by SPA inhibits DNA re-licensing resulting in death in the subsequent cell cycle.21,22 Haffner et al. showed that SPA generates transient double-strand DNA breaks (DSBs) in CRPC cells through the recruitment of AR and topoisomerase II beta (TOP2B) to androgen response elements (AREs).32 SPA downregulates oncogenes and upregulates tumor suppressor expression, inhibits expression of the ligand-independent AR variant, AR-V7and produces profound metabolic and gene expression changes in CRPC cells that can lead to activation of autophagy and ferroptosis.33-35
Based on this extensive preclinical data, we instituted a clinical program to demonstrate the safety and efficacy of SPA, a treatment we have termed Bipolar Androgen Therapy (BAT), in men with metastatic CRPC. To date we have completed 4 studies: (1) a proof-of-concept pilot (n = 14), (2) RESTORE—testing efficacy and safety of BAT in men with CRPC progressing on ADT, abiraterone or enzalutamide (n = 88), (3) TRANSFORMER—a randomized study comparing BAT to enzalutamide in men progressing on abiraterone (n = 195), and (4) COMBAT—evaluating sequential BAT and nivolumab (n = 44).36-40
What is Bipolar Androgen Therapy (BAT)?
Preclinical in vitro and in vivo studies using human CRPC models suggest that a dosing regimen that produces supraphysiologic testosterone (ie, SPA) levels is critical for achieving the desired pharmacologic effect on the target CRPC cells.33 Thus, BAT involves the administration of sufficient testosterone to achieve a supraphysiologic serum level in men with CRPC who are progressing on chronic ADT ± ARSI. The term “bipolar” is used because BAT involves rapid cycling between 2 polar extremes: from supraphysiologic back to near-castrate serum testosterone levels over a treatment cycle achieved through the administration of 400 mg of testosterone cypionate, a generic, FDA-approved depot form of testosterone that is injected intramuscularly into the buttocks.41 Testosterone can also be delivered via transdermal, transbuccal, intranasal, or oral preparations. However, achieving supraphysiologic levels of testosterone with these preparations would be cost-prohibitive and likely require non-FDA-approved dosing.
*Assessing Response to BAT in Clinical Studies
*Clinical Studies of BAT in Men with CRPC
-Pilot Study of BAT
-Results From the RESTORE Study
-Results From the TRANSFORMER Study
-The COMBAT Trial
*BAT Can Restore Sensitivity/Overcome Resistance to Antiandrogen Therapy
*Predictors of Response to BAT
*BAT Can Be Given Safely to Men With Asymptomatic CRPC
*BAT Improves Quality of Life in Men With CRPC
Conclusions/Recommendations
Our cumulative clinical experience over the past 10 years treating >250 CRPC patients establishes the meaningful clinical activity and safety of BAT and supports additional studies to determine its optimal clinical integration. Key findings from these clinical studies are that BAT (a) can be safely administered to asymptomatic patients with mCRPC; (b) does not produce symptomatic disease progression; (c) produces sustained PSA and objective responses in 30%-40% of patients; and (d) can re-sensitize and prolong response to subsequent antiandrogen therapy.34,36-40 While ADT for advanced PCa often produces debilitating sexual and metabolic side effects, another highly significant feature of this approach is that BAT can make men feel remarkably better by decreasing fatigue, increasing physical activity, and restoring libido and sexual function. BAT can also increase skeletal muscle tone and decrease visceral and subcutaneous fat.48 Thus, the incorporation of inexpensive, high-dose testosterone via BAT into the treatment paradigm for men with CRPC has the potential to improve quality of life (QoL) and minimize morbidity from the metabolic sequelae produced by androgen ablative therapies. Patients who are interested in more information on BAT can be referred to a recent review written for a lay audience.48
Ongoing clinical trials are designed to assess the optimal way to sequence and combine BAT in PCa. Patients are encouraged to seek out and participate in such clinical trials when possible. For those without access to trials, there are 2 clinical settings in which BAT could be recommended based on the available clinical data. First, for asymptomatic patients who have initially progressed on ADT, BAT could be administered prior to starting an ARSI due to its marked ability to enhance subsequent response to these agents. Second, in men with CRPC progressing on abiraterone, BAT can be considered as part of sequential therapy with an antiandrogen based on results from the TRANSFORMER study. Importantly, BAT should always be given in conjunction with ongoing ADT. BAT is not to be used in patients with castration-sensitive disease outside of a clinical trial. BAT is also not currently recommended for use in patients with PCa bone pain as these patients are at risk for significant worsening of pain following testosterone injection. In those few patients who experienced pain flares in BAT clinical studies, we have observed that the flare usually occurs within 12-48 h post-testosterone injection. Pain can be treated with anti-inflammatory medications but may be severe enough to require narcotics. It typically resolves after ~1 week postBAT, when the testosterone level begins to fall. For those patients who do develop a pain flare on the first dose of BAT that resolves by the end of a 28-day cycle, consideration can be given to continue BAT for a second cycle. We have observed pain improvement or resolution that did not return with subsequent cycles of BAT. For those patients who continue to have pain at the end of the first 28-day cycle, BAT should be discontinued.
Future Directions
Although our initial results have been encouraging, with some men responding to BAT for several years, the median duration of progression-free survival across these studies is approximately 6-9 months. Thus, rational combinatorial approaches are needed that can further enhance and prolong the efficacy of BAT. Combinations based on the current understanding of the profound effects of androgen on PCa cell gene expression, metabolism, and immune microenvironment are being explored in preclinical and clinical studies. These include BAT in combination with Nivolumab (NCT03554317),40 olaparib (NCT03516812), 223Radium (NCT04704505), and carboplatin (NCT03522064). Finally, although BAT has activity as a single agent, more importantly, the sequence of BAT→ARSI (such as enzalutamide) should be considered as a therapeutic continuum. On this basis, the efficacy of repeat cycling between BAT and enzalutamide is being tested in the Sequential Testosterone and Enzalutamide Prevents Unfavorable Progress (STEP-UP) trial, Fig. 4. Further studies are required to assess the disease stage and optimal timing for sequencing between BAT and ARSI based on an understanding of PCa cells adaptive response to changing AR activity in the tumor microenvironment.
Samuel R. Denmeade*,Laura A. Sena, Hao Wang, Emmanuel S. Antonarakis, Mark C. Markowski
Abstract
Inhibition of androgen receptor (AR) signaling has been the mainstay of treatment of advanced prostate cancer (PCa) for the past 80 years. Combination and sequential AR-inhibiting therapies are highly effective palliative therapy, but they are not curative. All patients eventually develop resistance to primary castrating therapy [ie, castration-resistant PCa (CRPC)]. At this point, they are treated with subsequent lines of secondary AR inhibitory therapies. However, resistance to these agents also develops and patients progress to a state we have termed complete androgen inhibition-resistant PCa. This phase of the disease is associated with poor prognosis. At this point, treatment shifts to non-hormonal cytotoxic therapies (eg, chemotherapy and radiopharmaceuticals). However, the majority of PCas remain addicted to signaling through AR throughout the course of the disease. Resistant PCa cells adaptively upregulate AR activity, despite castration and AR inhibitors, via mechanisms such as AR overexpression, gene amplification, mutation, and expression of ligand-independent variants to permit sustained liganded and non-liganded AR signaling. Studies dating back nearly 30 years indicate that high expression of AR induced by prolonged castration becomes a vulnerability of CRPC cells in vitro and in mouse xenografts to supraphysiologic androgen (SPA), which induces cell death and growth arrest in this context. Based on these studies, we developed a counterintuitive treatment called bipolar androgen therapy (BAT) for patients with CRPC, in which SPA is administered intermittently to result in the cycling of serum testosterone from the polar extremes of supraphysiologic to near-castrate levels. This rapid cycling is intended to disrupt the adaptive AR regulation associated with chronic exposure to high or low levels of testosterone, while simultaneously targeting the spectrum of AR expression present in heterogeneous CRPC tumors. We have now tested BAT in >250 patients with CRPC. Here we present a review of these clinical studies, which have demonstrated collectively that BAT can be safely given to men with CRPC, improves the quality of life, and produces therapeutic responses in ~30% of patients. As expected, resistance to BAT is associated with adaptive downregulation of AR expression. Intriguingly, this downregulation is associated with the restoration of sensitivity to subsequent AR inhibitor therapies.
Introduction
The Current Treatment Paradigm
In 1941, Dr. Charles Huggins reported on the remarkable palliative benefit of surgical and medical castration in men with symptomatic, metastatic prostate cancer (PCa). Since that discovery, inhibition of androgen receptor (AR) function through androgen deprivation (ADT) and direct AR inhibition has remained the mainstay of treatment.1,2 The current treatment paradigm for metastatic PCa is to treat men with ADT in combination with AR signaling inhibitors (ARSI) or chemotherapy until disease progression. From the very outset of ADT use, it was recognized that all men eventually develop resistance to primary ADT, a disease stage known as castration-resistant PCa (CRPC). This resistance was presumed to be due to sustained AR signaling via non-prostate sources of androgens.2 Once the patient develops CRPC, additional AR inhibiting therapies are administered with decreasing effectiveness as more lines of therapy are given.3,4 In addition to therapeutic resistance, chronic exposure to ADT leads to excess morbidity and, in a subset of men, may lead to transdifferentiation to a more aggressive and lethal neuroendocrine phenotype.5
A number of ARSIs have been developed as first-line therapy in combination with or after ADT aimed at further blocking androgen signaling through AR.6 These include the CYP17 androgen-synthesis inhibitor abiraterone and antiandrogens enzalutamide, apalutamide, and darolutamide. Both abiraterone and enzalutamide received initial FDA approval based on modest survival benefit vs. placebo in men with mCRPC post-chemotherapy and subsequently in men treated pre-chemotherapy based on the results of the COU-AA-302 (abiraterone) and PREVAIL (enzalutamide) studies, Table 1. 7-10
The effectiveness of first-line combination androgen blockade was revisited with multiple trials such as LATITUDE (abiraterone), STAMPEDE (abiraterone), ARCHES (enzalutamide), and TITAN (apalutamide) each demonstrating a significant survival advantage for combination therapy compared to ADT alone in men with high risk and metastatic PCa.11-14 Recent results from the ARASENS trial also demonstrated a survival advantage for “triplet” therapy consisting of ADT + docetaxel + darolutamide vs. the “doublet” of ADT + docetaxel.15 While these trials have shown significant improvement in survival vs. the control arm, once patients develop radiographic progression, survival is relatively short with a median duration of survival in the range of 18-24 months.11,12
Additionally, emerging data documents a significant reduction in response rate and response duration with sequential use of abiraterone or enzalutamide as “second or third-line” ARSI therapy. Results from a series of small studies evaluating the use of enzalutamide after progression on abiraterone show a marked decrease in PSA PFS, time to progression, and objective response.16-19 Broadly, ~95% of patients respond to initial androgen ablative therapy, with ~65% response to first-line ARSI and ~25% response to second and further lines of ARSI therapy. Evaluation of patient biopsies and autopsy studies demonstrates that CPRC cells resistant to ARSI continue to engage in AR signaling and adapt to chronic exposure to low testosterone through a progressive, auto-regulatory increase in AR expression to sufficient levels to restore AR axis activity even in the absence of ligand.20-22 At each stage, resistance first manifests as a sustained rise in the androgen-responsive gene PSA, consistent with the reactivation of a functioning AR axis.
Rationale for Supraphysiologic Testosterone as Therapy for CRPC
A major factor driving resistance to ADT is the ability of PCa cells to adapt to chronic low androgen conditions by upregulating AR activity through overexpression, gene amplification, and expression of transcriptionally active AR variants that lack the ligand-binding domain, Fig. 1A, 1B. 23-27 Data from a variety of studies has demonstrated that AR expression persists even in men with CRPC who have died from PCa despite having received chronic ADT and multiple types of ARSI.20,25 Chen et al. demonstrated that PCa cell lines adapt to serial passage in castrated mice through an auto-regulatory increase in AR expression that is sufficient to induce resistance to both ADT and the anti-androgen bicalutamide.28 Isaacs et al. documented that AR levels increased 30-90 fold in CRPC cell lines and clinical samples compared to normal prostate cells.29 While this marked upregulation of AR can drive resistance to ADT, it also creates a therapeutic vulnerability to treatment with supraphysiologic androgen (SPA).28-30 SPA can lead to growth arrest or cell death in CRPC cell models. This paradoxical effect initially was extensively demonstrated by the work of Dr. Shutsung Liao, whose laboratory showed that PCA cells adapted to grow in low androgen conditions had high AR levels and were growth-inhibited by SPA in vivo.31 Over time, these xenografts became resistant to SPA through downregulation of the AR, making them once again sensitive to ADT.
Several complementary mechanisms for this paradoxical effect of SPA have been described. Isaacs et al. demonstrated that AR is a DNA licensing factor that plays a critical role in DNA replication and must be degraded as the cell goes through cycle.21,22,29 AR over-stabilization by SPA inhibits DNA re-licensing resulting in death in the subsequent cell cycle.21,22 Haffner et al. showed that SPA generates transient double-strand DNA breaks (DSBs) in CRPC cells through the recruitment of AR and topoisomerase II beta (TOP2B) to androgen response elements (AREs).32 SPA downregulates oncogenes and upregulates tumor suppressor expression, inhibits expression of the ligand-independent AR variant, AR-V7and produces profound metabolic and gene expression changes in CRPC cells that can lead to activation of autophagy and ferroptosis.33-35
Based on this extensive preclinical data, we instituted a clinical program to demonstrate the safety and efficacy of SPA, a treatment we have termed Bipolar Androgen Therapy (BAT), in men with metastatic CRPC. To date we have completed 4 studies: (1) a proof-of-concept pilot (n = 14), (2) RESTORE—testing efficacy and safety of BAT in men with CRPC progressing on ADT, abiraterone or enzalutamide (n = 88), (3) TRANSFORMER—a randomized study comparing BAT to enzalutamide in men progressing on abiraterone (n = 195), and (4) COMBAT—evaluating sequential BAT and nivolumab (n = 44).36-40
What is Bipolar Androgen Therapy (BAT)?
Preclinical in vitro and in vivo studies using human CRPC models suggest that a dosing regimen that produces supraphysiologic testosterone (ie, SPA) levels is critical for achieving the desired pharmacologic effect on the target CRPC cells.33 Thus, BAT involves the administration of sufficient testosterone to achieve a supraphysiologic serum level in men with CRPC who are progressing on chronic ADT ± ARSI. The term “bipolar” is used because BAT involves rapid cycling between 2 polar extremes: from supraphysiologic back to near-castrate serum testosterone levels over a treatment cycle achieved through the administration of 400 mg of testosterone cypionate, a generic, FDA-approved depot form of testosterone that is injected intramuscularly into the buttocks.41 Testosterone can also be delivered via transdermal, transbuccal, intranasal, or oral preparations. However, achieving supraphysiologic levels of testosterone with these preparations would be cost-prohibitive and likely require non-FDA-approved dosing.
*Assessing Response to BAT in Clinical Studies
*Clinical Studies of BAT in Men with CRPC
-Pilot Study of BAT
-Results From the RESTORE Study
-Results From the TRANSFORMER Study
-The COMBAT Trial
*BAT Can Restore Sensitivity/Overcome Resistance to Antiandrogen Therapy
*Predictors of Response to BAT
*BAT Can Be Given Safely to Men With Asymptomatic CRPC
*BAT Improves Quality of Life in Men With CRPC
Conclusions/Recommendations
Our cumulative clinical experience over the past 10 years treating >250 CRPC patients establishes the meaningful clinical activity and safety of BAT and supports additional studies to determine its optimal clinical integration. Key findings from these clinical studies are that BAT (a) can be safely administered to asymptomatic patients with mCRPC; (b) does not produce symptomatic disease progression; (c) produces sustained PSA and objective responses in 30%-40% of patients; and (d) can re-sensitize and prolong response to subsequent antiandrogen therapy.34,36-40 While ADT for advanced PCa often produces debilitating sexual and metabolic side effects, another highly significant feature of this approach is that BAT can make men feel remarkably better by decreasing fatigue, increasing physical activity, and restoring libido and sexual function. BAT can also increase skeletal muscle tone and decrease visceral and subcutaneous fat.48 Thus, the incorporation of inexpensive, high-dose testosterone via BAT into the treatment paradigm for men with CRPC has the potential to improve quality of life (QoL) and minimize morbidity from the metabolic sequelae produced by androgen ablative therapies. Patients who are interested in more information on BAT can be referred to a recent review written for a lay audience.48
Ongoing clinical trials are designed to assess the optimal way to sequence and combine BAT in PCa. Patients are encouraged to seek out and participate in such clinical trials when possible. For those without access to trials, there are 2 clinical settings in which BAT could be recommended based on the available clinical data. First, for asymptomatic patients who have initially progressed on ADT, BAT could be administered prior to starting an ARSI due to its marked ability to enhance subsequent response to these agents. Second, in men with CRPC progressing on abiraterone, BAT can be considered as part of sequential therapy with an antiandrogen based on results from the TRANSFORMER study. Importantly, BAT should always be given in conjunction with ongoing ADT. BAT is not to be used in patients with castration-sensitive disease outside of a clinical trial. BAT is also not currently recommended for use in patients with PCa bone pain as these patients are at risk for significant worsening of pain following testosterone injection. In those few patients who experienced pain flares in BAT clinical studies, we have observed that the flare usually occurs within 12-48 h post-testosterone injection. Pain can be treated with anti-inflammatory medications but may be severe enough to require narcotics. It typically resolves after ~1 week postBAT, when the testosterone level begins to fall. For those patients who do develop a pain flare on the first dose of BAT that resolves by the end of a 28-day cycle, consideration can be given to continue BAT for a second cycle. We have observed pain improvement or resolution that did not return with subsequent cycles of BAT. For those patients who continue to have pain at the end of the first 28-day cycle, BAT should be discontinued.
Future Directions
Although our initial results have been encouraging, with some men responding to BAT for several years, the median duration of progression-free survival across these studies is approximately 6-9 months. Thus, rational combinatorial approaches are needed that can further enhance and prolong the efficacy of BAT. Combinations based on the current understanding of the profound effects of androgen on PCa cell gene expression, metabolism, and immune microenvironment are being explored in preclinical and clinical studies. These include BAT in combination with Nivolumab (NCT03554317),40 olaparib (NCT03516812), 223Radium (NCT04704505), and carboplatin (NCT03522064). Finally, although BAT has activity as a single agent, more importantly, the sequence of BAT→ARSI (such as enzalutamide) should be considered as a therapeutic continuum. On this basis, the efficacy of repeat cycling between BAT and enzalutamide is being tested in the Sequential Testosterone and Enzalutamide Prevents Unfavorable Progress (STEP-UP) trial, Fig. 4. Further studies are required to assess the disease stage and optimal timing for sequencing between BAT and ARSI based on an understanding of PCa cells adaptive response to changing AR activity in the tumor microenvironment.
